Tricyclic Antidepressants Amitriptyline and Desipramine Induced Neurotoxicity Associated with Parkinson's Disease.

Recent studies report that a history of antidepressant use is strongly correlated with the occurrence of Parkinson's disease (PD). However, it remains unclear whether antidepressant use can be a causative factor for PD. In the present study, we examined whether tricyclic antidepressants amitriptyline and desipramine can induce dopaminergic cell damage, both in vitro and in vivo. We found that amitriptyline and desipramine induced mitochondria-mediated neurotoxicity and oxidative stress in SH-SY5Y cells. When injected into mice on a subchronic schedule, amitriptyline induced movement deficits in the pole test, which is known to detect nigrostriatal dysfunction. In addition, the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta was reduced in amitriptyline-injected mice. Our results suggest that amitriptyline and desipramine may induce PD-associated neurotoxicity.

Identification of hepatic phospholipidosis inducers in sandwich-cultured rat hepatocytes, a physiologically relevant model, reveals altered basolateral uptake and biliary excretion of anionic probe substrates.

Drug-induced phospholipidosis (PLD) is characterized by phospholipid accumulation within the lysosomes of affected tissues, resulting in lysosomal enlargement and laminar body inclusions. Numerous adverse effects and toxicities have been linked to PLD-inducing drugs, but it remains unknown whether drug-induced PLD represents a distinct toxicity or cellular adaptation. In silico and immortalized cellular models have been used to evaluate the PLD potential of new drugs, but these systems have some limitations. The aims of this study were to determine whether primary sandwich-cultured hepatocytes (SCH) can serve as a sensitive and selective model to evaluate hepatic drug-induced PLD, and to evaluate the impact of PLD on the uptake and biliary excretion of probe substrates, taurocholate (TC) and rosuvastatin (RSV). Rat SCH were cultured for 48 h with prototypic hepatic PLD-inducing drugs, amiodarone (AMD), chloroquine (CHQ), desipramine (DES), and azithromycin (AZI), as well as the renal PLD inducer gentamicin (GTM). LysoTracker Red localization and transmission electron microscopy indicated enlarged lysosomal compartments and laminar body inclusions in SCH treated with AMD, CHQ, DES, and AZI, but not GTM, relative to control. PLD resulted in a 51-92% decrease in the in vitro biliary clearance of both TC and RSV; the biliary excretion index significantly decreased for TC from 88 to 35-73%. These data suggested that PLD significantly reduced both organic anion transporting polypeptide-mediated uptake, and bile salt export pump-mediated biliary transport processes. The current study demonstrates that the rat SCH system is a promising model to study hepatic PLD in vitro. Altered hepatic transport of anionic substrates secondary to drug-induced PLD is a novel finding.

Stimulatory effect of antidepressant drug pretreatment on progression of B16F10 melanoma in high-active male and female C57BL/6J mice.

The effect of a two-week desipramine or fluoxetine (10 mg/kg, i.p.) pretreatment on B16F10 melanoma growth in 3-5 month old female and male C57BL/6J mice differing in behavioral characteristics (high- vs. low-active) was compared. Antidepressant pretreatment increased metastasis formation, shortened the survival, decreased splenocyte anti-tumor natural killer cell cytotoxicity (in vitro), and the pro-inflammatory cytokine IL-12p40, IFN-γ production while it increased anti-inflammatory cytokine IL-10 production in high-active males (desipramine) or females (fluoxetine). The obtained results emphasize a stimulatory effect of pretreatment with antidepressants on progress of B16F10 melanoma that depends on gender and behavioral characteristics of the animal.

Chromosomal aberrations induced by imipramine and desipramine in mouse.

Imipramine (IMI) and desipramine (DES) are two drugs widely used for the treatment of depression as well as for other diseases. In the present study, we determined their capacity to induce chromosomal aberrations in mouse bone marrow cells. Three doses of each compound were tested and their results were compared with the frequency of chromosomal aberrations obtained in a control group as well as with a group treated with cyclophosphamide. Our results showed a significant increase in chromosome damage with the doses tested for each compound: 7, 20, and 60 mg/kg in the case of IMI, and 2, 20, and 60 mg/kg as regards DES. This last drug induced stronger chromosomal damage than IMI. Our results agree with previous studies regarding the induction of micronuclei and sister chromatid exchanges by the drugs in mouse and suggest caution with respect to their use in long-term treatments.

Age-dependent stimulatory effect of desipramine and fluoxetine pretreatment on metastasis formation by B16F10 melanoma in male C57BL/6 mice.

Although recent data may provide theoretical support for the preventive use of antidepressants in cancer patients, so far no study has demonstrated the clinical benefits of such strategies in the general population of cancer patients [39, 41]. Moreover, an association between antidepressant use and the risk of tumor promotion could neither be excluded nor established. The aim of this study was to compare the effect of desipramine (a tricyclic antidepressant, TCA) and fluoxetine (a selective serotonin reuptake inhibitor, SSRI) on tumor growth of the mouse B16F10 transplanted melanoma in "young" 6-9 month old and "aged" 18-23 month old male C57BL/6 mice. Drugs were administered daily at a dose of 10 mg/kg, ip, for two weeks and tumor cells were inoculated 2 h after the last antidepressant administration. Control animals were treated with saline. Tumor growth was significantly slower in aged than in young saline-treated control animals. Pretreatment with desipramine dramatically promoted metastasis formation and increased mortality rate but inhibited primary tumor growth in young males. On the other hand, both antidepressants increased primary tumor growth in aged animals, whereas metastasis was only moderately promoted. To determine the effect of antidepressant drug pretreatment and tumor progress on some parameters of cell-mediated immunity (proliferative activity and cytokine production by splenocytes) and angiogenesis, vascular endothelial growth factor (VEGF) and metalloproteinase (MMP)-9 plasma levels were established. The prometastatic effect of desipramine in young animals was connected with an increase of VEGF and MMP-9 plasma levels.

Micronuclei induced by imipramine and desipramine in mice: a subchronic study.

Depression is a common disease that may cause severe damage to human health. Imipramine (IMI) and desipramine (DES) are medicaments used for treatment, yet studies on their genotoxic potential have given controversial results. Therefore, we designed the present assay to determine their effect as inducers of micronucleated polychromatic erythrocytes (MNPE) and micronucleated normochromatic erythrocytes (MNNE) in mice. The study was carried out in animals administered daily with the compounds for 4 weeks, and the determination of micronuclei was done each week. We also evaluated the bone marrow cytotoxicity induced by the chemicals. Besides, the same determinations were carried out in the following 4 consecutive weeks, but in this period the animals were not treated with the tested compounds. Our results showed a significant increase in both MNPE and MNNE induced by both compounds from the first week of administration. At the fourth week, IMI increased three times the control level, while the effect of DES was about seven times such level. In the second, 4-week phase, we observed a reduction in the rate of micronuclei approaching the control level. We also detected a bone marrow-mitotic division decrease by the evaluated chemicals. Our results point to the need for cautiousness in the clinical use of the compounds as well as for testing the effect in patients under treatment.

Desipramine-induced apoptosis in human PC3 prostate cancer cells: activation of JNK kinase and caspase-3 pathways and a protective role of [Ca2+]i elevation.

The antidepressant desipramine has been shown to induce a rise in cytosolic Ca2+ levels ([Ca2+]i) and cytotoxicity in human PC3 prostate cancer cells, but the mechanisms underlying its cytotoxic effect is unclear. Cell viability was examined by WST-1 assays. Apoptosis was assessed by propidium iodide staining and an increase in caspase-3 activation. Phosphorylation of protein kinases was analyzed by immunoblotting. Desipramine caused cell death via apoptosis in a concentration-dependent manner. Immunoblotting data revealed that desipramine activated the phosphorylation of c-Jun NH2-terminal kinase (JNK), but not extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). SP600125 (a selective JNK inhibitor) partially prevented cells from apoptosis. Pretreatment with BAPTA/AM, a Ca2+ chelator, to prevent desipramine-induced [Ca2+]i rises worsened desipramine-induced cytotoxicity. Immunoblotting data suggest that BAPTA/AM pretreatment enhanced desipramine-evoked JNK phosphorylation and caspase-3 cleavage. The results suggest that in PC3 cells, desipramine caused apoptosis via inducing JNK-associated caspase-3 activation, and [Ca2+]i rises may slow down or alleviate desipramine-induced cytotoxicity.

In vitro biotransformation of amitriptyline and imipramine with rat hepatic S9 fraction: evaluation of the toxicity with Spirotox and Thamnotoxkit F Tests.

Pharmaceutical products, as well as their related metabolites, end up in the aquatic environment after use. Little is known about the effects and the hazard of exposure to drugs for aquatic organisms. This study was designed to assess the ecotoxicity of amitriptyline (AMI), imipramine (IMI), and their metabolites. The tested drugs were very toxic to the protozoan Spirostomum ambiguum and the crustacean Thamnocephalus platyurus with the LC50 values around 1 mg l(-1). Moreover, simple additivity occurs between the drugs and their N-desmethyl metabolites. Tested compounds were incubated with S9 rat hepatocyte fraction at 37 degrees C for 4 hours. Unchanged drugs and metabolites were determined using high-pressure liquid chromatography-photodiode array detector. AMI and IMI were biotransformed almost completely. Three AMI and IMI metabolites were detected: desmethyl-, didesmethyl-, and N-oxide. The toxicity of the deproteinated reaction mixtures (TU) was compared to the toxicity equivalency units (TEU) calculated based on the concentrations of the drugs and their LC50 values. It has been demonstrated that the toxicity of mixture of metabolites to Spirotox and Thamnotoxkit F is higher than the predicted value calculated from the concentrations of the drugs and their N-desmethylated derivatives in the sample. The results indicate that the harmfulness of the drug metabolites should be taken into consideration in the ecotoxicological studies.

A novel approach for predicting antidepressant-induced sexual dysfunction in rats.

RATIONALE: Sexual dysfunction is associated with antidepressant discontinuation. Therefore, there is a need for models that predict antidepressant-induced sexual dysfunction. OBJECTIVE: To develop a predictive method for evaluating antidepressant-induced sexual dysfunction. METHODS: Male Sprague-Dawley rats were allowed access to sexually receptive females during a single overnight mating session and then treated with antidepressants known to produce differing levels of sexual dysfunction in the clinic. Two to three weeks later, following either acute, subchronic (7-day), or chronic (14-day) antidepressant treatment, rats were observed for penile erections (PE) in the presence of sexually receptive females that were not accessible for contact but served as visual, auditory, and olfactory stimuli in the testing area. RESULTS: Chronic treatment of fluoxetine (10 mg/kg), desipramine (10 mg/kg), and bupropion (20 mg/kg) reduced the number of PE 71, 53, and 8%, respectively, relative to vehicle-treated rats. This rank order of the compounds' propensity for reducing PE is comparable to the rank order of the compounds' ability to produce sexual dysfunction during antidepressant treatment in the clinic. Additionally, drugs used to treat antidepressant-induced sexual dysfunction in the clinic, such as sildenafil, yohimbine, and dopamine agonists, were also effective in attenuating the deficits in the number of noncontact PE produced by chronic fluoxetine treatment. CONCLUSIONS: Taken together, this model represents a novel approach for predicting antidepressant-induced sexual dysfunction in rats, which parallels the pattern of reports of sexual dysfunction in the clinic associated with different antidepressant treatments and the ability of adjunct treatment to reverse the sexual impairments produced by antidepressants.

Desipramine-induced Ca2+ movement and cytotoxicity in PC3 human prostate cancer cells.

The effect of the antidepressant desipramine on intracellular Ca(2+) movement and viability in prostate cancer cells has not been explored previously. The present study examined whether desipramine could alter Ca(2+) handling and viability in human prostate PC3 cancer cells. Cytosolic free Ca(2+) levels ([Ca(2+)](i)) in populations of cells were measured using fura-2 as a probe. Desipramine at concentrations above 10 microM increased [Ca(2+)](i) in a concentration-dependent manner. The responses saturated at 300 microM desipramine. The Ca(2+) signal was reduced by half by removing extracellular Ca(2+), but was unaffected by nifedipine, nicardipine, nimodipine, diltiazem or verapamil. In Ca(2+)-free medium, after treatment with 300 microM desipramine, 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor) failed to release Ca(2+) from endoplasmic reticulum. Conversely, desipramine failed to release more Ca(2+) after thapsigargin treatment. Inhibition of phospholipase C with U73122 did not affect desipramine-induced Ca(2+) release. Overnight incubation with 10-800 microM desipramine decreased viability in a concentration-dependent manner. Chelation of cytosolic Ca(2+) with BAPTA did not reverse the decreased cell viability. Collectively, the data suggest that in PC3 cells, desipramine induced a [Ca(2+)](i) increase by causing Ca(2+) release from endoplasmic reticulum in a phospholipase C-independent fashion and by inducing Ca(2+) influx. Desipramine decreased cell viability in a concentration-dependent, Ca(2+)-independent manner.

Chronic treatment with clomipramine and desipramine induces deficit in long-term visuo-spatial memory of rats.

Although the effects of antidepressants in brain neurochemistry have been extensively studied, there are scarce and inconsistent data on the effect of these drugs in learning and memory. The authors studied the effect of daily administration of a single dose of either clomipramine or desipramine, two monoamine-reuptake-inhibitors with preferential serotonergic and noradrenergic profiles, respectively, during 15 days, on the visuo-spatial memory of adults rats measured through their performance in an eight-arm radial maze. Rats receiving 10 mg/kg i.p. daily of clomipramine or desipramine, 30 min before testing, committed a significantly greater number of errors than saline-treated control rats throughout the duration of the test (5 sessions, 15 days), excepting for session one (after 3 days of testing) where there were no differences between the 3 groups of rats. Results indicated that both serotonergic and noradrenergic antidepressants could impair long-term visuo-spatial memory in the rat, whereas inducing no changes in working memory, effects that are likely related to changes in brain monoamine metabolism induced by the antidepressant drugs.

Sister chromatid exchanges produced by imipramine and desipramine in mouse bone marrow cells treated in vivo.

Imipramine and desipramine are two widely used tricyclic antidepressants which have shown conflicting results in regard to their in vitro genotoxic evaluation. The aim of this investigation was to determine the capacity of these compounds to induce in vivo sister-chromatid exchanges (SCEs) in mouse bone marrow cells. For each compound, the animals were organized in five groups constituted by five individuals. They were intraperitoneally (ip) administered with the test substances as follows: a negative control group treated with 0.4 ml of distilled water, a positive control group administered with cyclophosphamide (70 mg/kg), three groups treated with imipramine (7, 20 and 60 mg/kg), and three other groups treated with desipramine (2, 20 and 60 mg/kg). The general procedure included the subcutaneous implantation to each mouse of a 5-bromodesoxyuridine tablet (45 mg), and 1 h later, the administration of the chemicals involved. Twenty-one hours after the tablet implantation, the mice received colchicine, and 3 h later their femoral bone marrow was obtained in KCL, fixed, and stained with the Hoechst-Giemsa method. The results showed that both compounds were SCE inducers, starting from the second tested dose. The response of these compounds was dose-dependent, and showed that the highest tested dose increased about four times the SCE control level. The cellular proliferation kinetics was not affected by the chemicals, and the mitotic indexes were slightly diminished with the highest dose. These results indicate an in vivo genotoxic potential for both chemicals, and suggest that it is pertinent to follow their evaluation in other models.

Amitriptyline-induced loss of tight junction integrity in a human endothelial--smooth muscle cell bi-layer model.

Tricyclic antidepressants can, when taken in overdose, cause serious pulmonary failure such as the adult respiratory distress syndrome (ARDS). In this study we have examined the effects of some tricyclic antidepressants (amitriptyline, imipramine, nortriptyline and desipramine) on the viability and morphology of human endothelial and smooth muscle cells derived from umbilical cord. Effects of amitriptyline on endothelial cell fluidity, as well as permeability changes to an endothelial-smooth muscle cell bi-layer, were also studied. The tricyclic antidepressants induced acute, sub-lethal toxicity in both cell types above 100 microM as assessed by the MTT reduction assay. Morphological changes were also observed at these concentrations. Such changes were, however, absent at 33 microM and below. Amitriptyline did, however, cause a concentration-dependent fall in the electrical resistance of an endothelial-smooth muscle cell bi-layer, with significant effects already evident at 33 microM. All of these observed effects were fairly rapid and appeared within 5-15 min of exposure. The rapidity of these permeabilisation effects suggests potential membrane perturbations, since tricyclic antidepressants are lipophilic molecules with affinity for cell membranes. However, fluorescence anisotropy measurements showed no significant difference in membrane fluidity between amitriptyline-treated and control endothelial cells. Collectively, these data point to specific mechanisms of action of amitriptyline, and probably also the other tricyclic antidepressants studied, on endothelial permeability, which is a hallmark of ARDS. The data suggest that increased endothelial permeability could be due to impaired tight junction function.

Acute lung failure induced by tricyclic antidepressants.

Overdosing of several drugs, such as tricyclic antidepressants, salicylates, and opiates, is known to induce effects like those seen in patients with adult respiratory distress syndrome. By exposing isolated perfused and ventilated rat lungs via the perfusate to six different tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine, mianserine, and maprotiline), we investigated possible effects on ventilation (conductance and dynamic compliance), lung perfusion flow, and edema formation. The effects of these substances were pronounced and appeared within 15 min after exposure. Amitriptyline was studied in greater detail and caused a dose-related (0.01-1.0 mM) reduction in ventilation and perfusion flow. At the highest drug concentration pronounced lung edema was observed. Morphological studies were conducted with a transmission electron microscope. The microscopic preparations showed dose-related edema (amitriptyline 0.1 and 1.0 mM). The effects noted in our experimental studies are similar to those described in patients who have taken an overdose of tricyclic antidepressants. This emphasizes the possibility of a noncardiogenic edema component in these patients.

Nitric oxide contributes to desipramine-induced hypotension in rats.

1. Anesthetized rats received the TCA desipramine (DMI) 60 mg kg-1 i.p. Administration of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester-(L-NAME) 15 min after DMI reversed hypotension within 5 min (P < 0.05). In contrast to its beneficial effect on blood pressure, L-NAME worsened DMI-induced prolongation of the electrocardiographic QRS interval. Dexamethasone, an inhibitor of NOS induction, did not prevent DMI-induced hypotension. 2. To study the effect of L-NAME on survival, DMI was administered to anesthetized rats as a continuous i.v. infusion until death. Despite initially improving blood pressure, L-NAME decreased the mean survival time by 33% (P < 0.01) compared to control treatment. Administration of the nitric oxide (NO) donor nitroglycerine to rats during DMI infusion likewise decreased the mean survival time. 3. L-NAME partially reversed the hypotensive effect of nitroprusside in both anesthetized and awake rats. 4. These data suggest that NO production attributable to constitutive NOS (cNOS) activity aggravates the hypotension associated with DMI toxicity in the anesthetized rat, and contributes to the pathophysiology of this overdose. The shortened survival time produced by both increasing and decreasing NO production suggests that cNOS activity during DMI overdose is regulated and adaptive. Ongoing cNOS activity also contributed to nitroprusside-induced hypotension, and may represent a feature common to other drug-induced hypotensive states.

Ovine desipramine antibody fragments reverse desipramine cardiovascular toxicity in the rat.

STUDY OBJECTIVE: To develop a model of severe desipramine cardiovascular toxicity and to determine whether partial neutralization of the antigen by desipramine-specific Fab antibody fragments ameliorates its cardiovascular effects. METHODS: We administered desipramine to rats until the QRS interval tripled in duration and mean arterial pressure (MAP) was less than 100 mm Hg. Animals were then assigned to one of six groups: (1) no treatment, (2) normal saline solution control treatment (.9% NaCl infusion equal to the volume of Fab infusion), (3) nonimmune Fab control treatment (infusion of Fab equal to that in the 9.6% neutralization treatment), (4) 9.6% desipramine Fab (infusion of ovine desipramine Fab equal to 9.6% of an equimolar neutralization), (5) 19.2% desipramine Fab, and (6) 30.0% desipramine Fab. RESULTS: QRS-interval duration, heart rate, and MAP were recorded for 60 minutes. Animals in groups 1 through 3 demonstrated slow and incomplete improvement. Animals in groups 4 through 6 showed improvement in QRS-interval duration and heart rate within 4 minutes (P<.05) compared with untreated animals. A dose-response relationship was evident; animals given the highest dose of desipramine-specific Fab showed the greatest improvement. CONCLUSION: Partial neutralization of desipramine by specific Fab fragments produces rapid improvement of QRS-interval duration and heart rate in a rat model of severe desipramine toxicity.

Trypanocidal resistance in Trypanosoma evansi in vitro: effects of verapamil, cyproheptidine, desipramine and chlorpromazine alone and in combination with trypanocides.

A study was conducted in vitro to assess the ability of calcium antagonists to reverse trypanocidal resistance in Trypanosoma evansi. Susceptibility patterns of sensitive and resistant parasites were evaluated against calcium antagonists of several chemical classes (verapamil, cyproheptidine, desipramine and chlopromazine), alone and in combination with suramin, diminazene aceturate or melarsen oxide cyteamine. The putative resistance modulators were intrinsically antitrypanosomal, but were unable to reverse resistance to any of the trypanocides tested. It was thus concluded that resistance to these trypanocides in T. evansi may differ from drug resistance mechanisms occurring in cancer cells, malaria or in South American trypanosomosis, where calcium antagonists have successfully reversed resistance.

Effect of calcium chloride and 4-aminopyridine therapy on desipramine toxicity in rats.

BACKGROUND: Hypotension is a major contributor to mortality in tricyclic antidepressant overdose. Recent data suggest that tricyclic antidepressants inhibit calcium influx in some tissues. This study addressed the potential role of calcium channel blockade in tricyclic antidepressant-induced hypotension. METHODS: Two interventions were studied that have been shown previously to improve blood pressure with calcium channel blocker overdose. CaCl2 and 4-aminopyridine. Anesthetized rats received the tricyclic antidepressant desipramine IP to produce hypotension, QRS prolongation, and bradycardia. Fifteen min later, animals received CaCl2, NaHCO3, or saline. In a second experiment, rats received tricyclic antidepressant desipramine IP followed in 15 min by 4-aminopyridine or saline. RESULTS: NaHCO3 briefly (5 min) reversed hypotension and QRS prolongation. CaCl2 and 4-aminopyridine failed to improve blood pressure. The incidence of ventricular arrhythmias (p = 0.004) and seizures (p = 0.03) in the CaCl2 group was higher than the other groups. CONCLUSION: The administration of CaCl2 or 4-aminopyridine did not reverse tricyclic antidepressant-induced hypotension in rats. CaCl2 therapy may possibly worsen both cardiovascular and central nervous system toxicity. These findings do not support a role for calcium channel inhibition in the pathogenesis of tricyclic antidepressant-induced hypotension.

Reduction of desipramine cardiotoxicity and prolongation of survival in rats with the use of polyclonal drug-specific antibody Fab fragments.

STUDY OBJECTIVE: Tricyclic antidepressants (TCAs) are a leading cause of death from intentional drug overdose. Available therapies are often unsatisfactory. In this study we evaluated the use of a high-affinity drug-specific polyclonal Fab fragment (TFab) as an antidote to desipramine toxicity. DESIGN: We gave anaesthetized rats under mechanical ventilation IV desipramine so that we might study the effect of TFab on survival or IP desipramine to facilitate study of the interaction of TFab and hypertonic sodium bicarbonate (NaHCO3), the standard clinical treatment for TCA overdose. INTERVENTIONS: For the study of the effects of TFab and NaHCO3 on survival, each rat was given a constant IV infusion of desipramine until it died, together with TFab 2 g/kg, bovine serum albumin, or .9% NaCl starting 5 minutes after the desipramine infusion. In the study of the interaction of TFab and NaHCO3, each rat received 30 mg/kg IP desipramine followed by TFab (molar TFab:desipramine ratio, .11), NaHCO3, TFab+NaHCO3, or NaCl at the time of maximal toxicity (15 minutes). RESULTS: In the survival protocol, QRS-interval duration, systolic blood pressure, and heart rate were significantly improved by TFab, and survival was prolonged by 58% compared with that in the albumin and NaCl groups (P < .001). The molar ratio of TFab to administered desipramine was .21. The unbound fraction of desipramine in serum at the time of death was reduced by TFab, but the unbound desipramine concentration was not, suggesting that TFab prolonged survival by delaying the increase in the unbound serum desipramine concentration. In the interaction protocol, neither TFab nor NaHCO3 was effective alone, but the combination significantly reduced QRS-interval prolongation (P = .001). CONCLUSION: These data demonstrate the efficacy of TFab in reducing desipramine-induced cardiovascular toxicity and prolonging survival. The pharmacokinetic effects of TFab in rats with severe desipramine toxicity were similar to those observed in sublethal desipramine toxicity. Therapeutic benefit is enhanced by the concurrent use of NaHCO3 and may be achieved despite binding only a fraction of the desipramine dose.